Young and healthy looking skin is a desirable attribute worldwide and the market for cosmetic products capable of improving our skin appearance is significant and growing.
As we age, our natural ability to maintain young and healthy looking skin diminishes and, consequently, our skin appearance changes in response to the biological processes that take place within the skin at the cellular level. Modulation of these processes at the skin surface via intervention of specific pathways with diverse cosmetic ingredients can improve skin health and appearance. Numerous examples of how cosmetic ingredients can modulate appearance via this type of intervention are well documented.
Increased cell proliferation and migration, as well as epidermal thickness are some of the traits associated with a younger and healthy looking skin phenotype. Among the various pathways leading to such traits, inhibition of the muscarinic cholinergic system, particularly the muscarinic 3 receptor, has been shown to increase cell proliferation and migration in healthy skin. See for example, Grando et al, “Keratinocyte muscarinic acetylcholine receptors: immunolocalization and partial characterization” Journal of Investigative Dermatology (1995), 104, 95-100; Ndoye et al. “Identification and mapping of keratinocyte muscarinic acetylcholine receptor subtypes in human epidermis” Journal of investigative Dermatology (1998) 111, 410-416; Nguyen et al “Synergistic control of keratinocyte adhesion through muscarinic and nicotinic acetylcholine receptor subtypes” Exp. Cell. Res. (2004) 294, 534-549; Kurzen et al. “The non-neuronal cholinergic system of human skin” Horm. Metab. Res. (2007) 39, 125-137.
Muscarinic receptor antagonists have been claimed in medications used to treat skin diseases. For example, WO0110427 describes the use of anti-muscarinic agents to treat skin disorders including psoriasis, atopic dermatitis, eczema, urticaria, acne, etc. WO09068876 describes the use of muscarinic receptor antagonists with antibacterial and sebum suppressive activities in the manufacture of medicaments to treat bacterial skin infections. Further, WO09150408 and WO09068876 describe the use of muscarinic receptor antagonists in compositions to treat acne and seborrhea, for example.
Various compositions comprising some N-aralkylcarbonyl-piperazine derivatives or related structures have been described, for example in US20070004750 (Dow AgroSciences, LLC); WO2006056752 (Aztrazeneca UK Limited); Zha et al., “Synthesis and structure-activity relationship studies for hydantoins and analogues as voltage-gated sodium channel ligands”, Journal of Medicinal Chemistry (2004) 47, 6519-6528; WO03037271 (Millenium Pharmaceuticals); WO9718203 (Merck Sharp and Dohme Limited); Carceller et al. “(Pyridylcyanomethyl)piperazines as orally active PAF antagonists”, Journal of Medicinal Chemistry (1992) 35, 4118-4134 and EP441226; Di Paco et al. “Derivatives of ethylphenylacetic acid. I”, Farmaco, Edizione Scientifica (1956) 11, 540-548; Hromatka et al. “The synthesis of new acylpiperazines”, Monatshefte fuer Chemie (1954) 85, 1208-1214; Ogino et al. “Muscarinic M3 receptor antagonists with (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxyphenylacetamide structures. Part 2”, Bioorganic and Medicinal Chemistry Letters (2003) 13, 2167-2172; WO09079392 and US2009069335 (Theravance Inc.). However the specific derivatives used are different from the compounds of our invention. Differences in molecular architecture will likely result in different physicochemical and biological properties. Our compounds, for example, contain up to a single tertiary amine functional group (although the tertiary amine may be replaced by a second amide at the R3 site), but contain no secondary amine functional groups. As our pH data demonstrates, in going from a solution containing a secondary amine compound (2.5% weight/volume) to a solution containing a tertiary amine compound (2.5% weight/volume), the pH decreases from 10.0 to 8.5 for N-aralkylcarbonyl-piperazines (1.5 pH unit decrease) and from 9.9 to 9.0 for N-aralkylcarbonyl-homopiperazines (0.9 pH unit decrease). This clearly demonstrates that our compounds are less basic than similar compounds (by “similar” is meant a compound exactly the same but wherein, for example, R3 is an alkyl group, such as methyl instead of hydrogen and that therefore defines a tertiary amine instead of a secondary amine; see Example 31 versus 30 or 34 versus 33) having secondary amines. That is, they are less basic relative to compounds which have the same structure, but differ in that they have a secondary amine in place of a tertiary amine. In general, compounds of the invention will provide a drop in basicity of at least 0.3 pH units, preferably 0.3-4.0 pH units relative to the noted compounds when measured in solution as defined below. Moreover, none of these compounds noted above are recognized for use as cosmetics providing personal care benefits.
The novel N-aralkylcarbonyl-piperazines and -homopiperazine compounds of the invention have several advantages for use in personal care compositions compared to N-aralkylcarbonyl-piperazine derivatives and muscarinic receptor antagonists described in the prior art. For example, compounds of the invention are not quaternized, which distinguishes them from some of the currently used muscarinic receptor antagonists, for example, oxyphenonium bromide, glycopyrrolate, ipatropium, and tiotropium to name a few. By “not quaternized” is meant that they do not have an additional bond attaching an alkyl group to the nitrogen atom of the tertiary amine which provides a permanent positive charge. Quaternized compounds are less desirable because they do not penetrate skin as effectively compared to when they are in an unquaternized form. The novel unquarternized N-aralkylcarbonyls of the invention are thus better suited for skin applications.
As noted, the novel N-aralkylcarbonyls of our invention are non-quaternized and contain a maximum of one tertiary amine group. Thus, in compounds of our invention (defined by Formula I below), for example, R3 may be alkyl (forming a compound with one amide and one tertiary amine group because of the alkyl at R3); or R3 may be a carbonyl group (C═O), forming a compound having amide groups at both N atoms. Further, because of the presence of at least one amide group (even if R3 is alkyl and forms a tertiary amine), the compounds of our invention have lower pKa and are less basic than other muscarinic receptor antagonists known in the art. More specifically, they are less basic than other muscarinic receptor antagonists reported which either contain at least one basic amine group (e.g., primary or secondary amine) and/or, if they have tertiary amines, do not comprise an amide bond (which provides an inductive effect lowering the electron density of other potential secondary and tertiary amines) and therefore do not obtain lowered pKa and basicity (measured by lower pH in solution). In short, compared to other muscarinic receptor antagonists containing cyclic structures with secondary or tertiary amine (alkylpyrrollidine, alkylpiperidine, N-alkyl pyrrolidine, N-alkylpiperidine, etc.), the novel compounds of our invention have lower pKa and are less basic, as measured by dissolving equimolar amounts of inventive or comparative compounds in organic solvent and diluting with sufficient water to provide a 1 to 5% solution, preferably 2 to 4% solution (weight/volume) of the compound in the water-organic solvent homogeneous solution. Preferably, the drop in pH between comparative compound and inventive compound, when measured in solution, will be 0.3 to 4 pH units.
Specifically, for example, the pH of a 2.5% solution of the tertiary N-aralkylcarboxamido-piperazine (Example 3, ID 3c) is 8.5 compared to its corresponding secondary amine structure (N-methyl to N—H replacement) which has a pH of 10.0; this represents a 1.5 pH unit decrease from comparative secondary amine (sec) to inventive tertiary amine (tert) compound; and the pH of a 2.5% solution of the tertiary N-aralkylcarbonyl-homopiperazine (Example 5, ID 3e) is 9.0 compared to its corresponding secondary amine structure which has a pH of 9.9; this represents a 0.9 pH unit decrease from sec to tert. This clearly demonstrates that compounds of the invention are less basic than similar compound with corresponding secondary amines.
Some examples of piperazine compounds which are disclosed and which differ from those of the invention because of the presence of primary or secondary amines include WO 2009/079392 (amidine), US 2009/069335 (guanidine), compounds in Ogino et al., Bioorganic & Medicinal chemistry Letters (BMCL) 13 (2003), 2167-217 (diofluoro compounds with primary and/or secondary amines). In US 2008/269190 is disclosed a compound where the piperidine group is quaternized to form an ammonium group. These quaternized-piperidine ammonium compounds represent a different class of compounds with different particularities compared to their corresponding secondary or tertiary (non-quaternized) counterparts. Further, the ammonium structures have a permanent positive change (quaternary). For skin applications such compounds penetrate less and are less desirable.
Generally compounds with high pKa (typically providing solutions of higher pH) are less desirable for skin compositions as they can be more corrosive and irritating to the skin. They can form charged species, which are difficult to formulate, and thus deliver less effectively to the skin. By contrast, novel compounds of our invention are milder to the skin (less basic), penetrate better because they are less charged, and are easier to formulate in personal care compositions. Further, the novel N-aralkylcarbonylcompounds of the invention do not contain ester functional groups, unlike many of the currently used muscarinic receptor antagonists such as oxybutynin, hyoscyamine, dicyclomine, and propiverine to name a few. Compounds with ester groups are less desirable for skin compositions since they are prone to hydrolysis once formulated, especially under high heat storage conditions. Our compounds contain tertiary amide bonds which are known to be more stable than their corresponding esters.